Our somatosensory system detects mechanical stimuli with exquisite sensitivity. We can feel the movement a single hair, discriminate two points on our fingertips with sub-millimeter accuracy, and differentiate changes in vibrational amplitude and frequency over several orders of magnitude. Additionally, our proprioceptors create a dynamic map of our bodies in space through vigilant monitoring of our muscles and tendons. My lab has been focusing on increasing our understanding of the distinct subtypes of mechanosensory neurons that exist, the molecular architecture underlying force transduction, and the physiological roles these molecules and cells play in touch and pain. Skin is our largest sensory organ. Through it we sense touch and temperature as well as warnings of potential damage. This is achieved through the activation of distinct classes of primary sensory neurons have their afferent nerve terminals in skin. Research over many decades has sought to link sensory neuron function, neurochemistry and morphology. We are leveraging advances in mouse genetics and imaging to identify neurons that are critically important for the sensation of mechanical pain. We have usedinvivofunctional imaging to identify a class of cutaneous sensory neurons that are selectively activated by high-threshold mechanical stimulation (HTMRs). We show that their optogenetic excitation evokes rapid protective and avoidance behaviors. Unlike other nociceptors, these HTMRs are fast-conducting A-fibers with highly specialized circumferential endings wrapping the base of individual hair follicles. Notably, we find that A-HTMRs innervate unique but overlapping fields and can be activated by stimuli as precise as the pulling of a single hair. Together, the distinctive features of this class of A-HTMRs appear optimized for accurate and rapid localization of mechanical pain. As highlighted above, great progress has been made researching model organisms. How well these studies translate to humans is an open question. The study of rare inherited conditions offers an alternative approach to gain a window into the genetic underpinnings of human physiology. As part of an ongoing screen of patients with undiagnosed neuromuscular disorders, we are collaborating with Carsten Bonmmann (NINDS) to study patients he has identified with profound but selective deficits in mechanosensation. We are combining exome sequencing, sensory testing, and functional imaging in humans with model systems studies in heterologous cell lines and mice. It is our hope that by doing so we will discovery new disease alleles while better understanding the basic biology that underlies mechanosensation. Along these lines, we recently identified and described patients with inherited mutations in the gene PIEZO2, a stretchgated ion channel shown to be critically important for the detection of mechanical stimuli. Quantitative assessment of these patients revealed alterations in the sensations of touch and proprioception that provided unique insights into the function of this important molecule and the impact of its loss on many aspects of life we take for granted.